Despite considerable progress in understanding the role of inflammation in atherosclerosis, it remains unclear what mechanisms drive the inflammation and how it is regulated. CXCL16 is a unique inflammatory chemokine, which possesses both membrane-anchored and secreted forms, and expressed on multiple cell lineages including macrophages, dendritic cells, endothelial cells and aortic smooth muscle cells. The receptor for CXCL16, CXCR6, is preferentially expressed by Th1 or Tc1 cells and is a differential marker of polarized Th1 cells. Importantly, CXCL16 is also a scavenger receptor expressed on macrophages and bind to phosphatidylserine and OxLDL. The expression of CXCL16 is enriched in atherosclerotic plaques. Recently we have found that CXCL16-Ig fusion protein treatment significantly reduces atherosclerosis in ApoE-/- mice. Thus, we hypothesize that CXCL16 may be a critical molecular link that couples dyslipidaemia with inflammation and play an important role in atherosclerosis. This application aims to understand the mechanisms by which CXCL16-Ig fusion protein ameliorates atherosclerosis and explore the effects of CXCL16-Ig in prevention and treatment of atherosclerosis. In addition, we have generated CXCL16-deficient mice and CXCL16 transgenic mice. We will study the role of CXCL16 in the leukocyte trafficking, lipid accumulation, and the inflammatory response during the progression of atherosclerosis using these mouse models, which will not only reveal the biological functions of CXCL16 and its contextual action in atherosclerosis, but also help understand the mechanisms underlying the protective effect of CXCL16-Ig fusion protein for atherosclerosis. This study is expected to provide novel insights into the pathological mechanisms of atherogenic responses. The findings may lead to new therapeutic approaches in prevention and treatment of atherosclerosis. PUBLIC HEALTH RELEVANCE: This project seeks to investigate CXCL16 as a therapeutic target for atherosclerosis. The findings will not only provide important information for understanding the pathogenesis of atherosclerosis but may also lead to new therapeutic approaches in prevention and treatment of atherosclerosis.